Project Summary: Response to exercise stress is a well-recognized predictor of outcome in heart disease. The overall goal of this K23 proposal to is build on my previous experience in this area to identify genetic and other predictors of response to exercise stress, and thereby begin to develop a new framework for approaching risk of sudden death due to arrhythmias. The Specific Aims will determine the role of defined and new polymorphisms in modulating variability in intermediate electrophysiologic phenotypes, including responses to exercise stress and intrinsic heart rate. In Specific Aim 1, I will phenotype QT and RR responses during exercise and recovery in normal subjects, and test the role of genetic polymorphisms in mediating variability in these responses. In Specific Aim 2, I will phenotype intrinsic QT and RR response during exercise and recovery in normal subjects, and test the role of genetic polymorphisms in mediating variability in these responses. In Specific Aim 3,1 will determine the effect of a QT-prolonging drug on intrinsic heart rate and QT interval. The resources for me to develop further as a clinical investigator and to test the hypotheses underlying these aims are in place. This award will enhance my skills as a clinical investigator through clinical research, a defined educational program, and a formal mentoring process in a highly supportive and productive research and mentoring environment. In this way, the likelihood is maximized that my goal of developing as an independent investigator with a robust research program will be achieved. Relevance: Sudden cardiac death kills 420,000 Americans each year. This research has the potential to permit identification of individuals at risk for sudden cardiac death and therefore has significant relevance to public health.